Treatment of male reproductive disorder

Abstract

The present invention relates to the use of ultrasound imaging techniques and computer implemented image processing methods for determining and assessing male infertility, as well as non-invasive diagnostic methods to identify and diagnose male infertility, such as hypogonadism (testosterone deficiency). Furthermore, the invention relates to methods of selecting male subjects for fertility treatment and methods for the treatment of these subjects.

1 . A computer-implemented method for assessing testicular function in a male subject, the method comprising:
 receiving one or more ultrasound images collected using contrast-enhanced ultrasound (CEUS) and/or super-resolution ultrasound (SRUS);   determining one or more testicular parameters from the one or more ultrasound images;   comparing the one or more parameters to one or more threshold values of the one or more parameters;   determining a difference between the one or more parameters and the one or more threshold values; and   outputting an indication of testicular function based on the comparison of the one or more parameters with the one or more threshold values.   
     
     
         2 . The computer-implemented method of  claim 1 , further comprising:
 determining a region of interest within the one or more ultrasound images and performing image-processing within the region of interest to determine the one or more testicular parameters.   
     
     
         3 . The computer-implemented method of  claim 2 , further comprising:
 outputting a diagnosis of hypogonadism based on the comparison of the one or more parameters with the one or more threshold values.   
     
     
         4 . The computer-implemented method of  claim 1 , wherein the one or more testicular parameters each comprise a measurement of microvessel morphology based on the one or more ultrasound images. 
     
     
         5 . The computer-implemented method of  claim 4 , wherein the method further comprises:
 receiving a sequence of microbubble ultrasound images;   processing the sequence of ultrasound images to localise individual microbubbles through a sequence multiple images and thereby determine a plurality of microbubble tracks; and   determining the measurement of microvessel morphology based on the determined microbubble tracks.   
     
     
         6 . The computer-implemented method of  claim 5 , wherein the method further comprises:
 processing the sequence of ultrasound images to correct for motion in the image by performing image registration across the sequence of images; and   generating a microvascular image based on the motion-corrected sequence of ultrasound images.   
     
     
         7 . The computer-implemented method of  claim 1 , wherein the one or more testicular parameters are selected from the list comprising:
 testicular microvessel density, testicular microvessel diameter, testicular microvascular flow, regularity or entropy of testicular microvascular flow, and/or testicular microvessel tortuosity, and spatial heterogeneity of these parameters.   
     
     
         8 . The computer-implemented method of  claim 1 , wherein the method further comprises:
 processing the one or more ultrasound images to determine a microvessel density of the left and/or right testes or the mean thereof;   comparing the determined microvessel density to a threshold representing a healthy control; and   outputting a diagnosis of hypogonadism when the determined microvessel density is reduced compared to the threshold representing a health control.   
     
     
         9 . The computer-implemented method of  claim 8 , wherein the method further comprises:
 processing the one or more ultrasound images to determine a mean microvessel density;   comparing the determined mean microvessel density to a microvessel density threshold representing a healthy control, wherein the threshold is between 0.05 and 0.15; and   outputting a diagnosis of hypogonadism when the determined microvessel density is below the microvessel density threshold.   
     
     
         10 . The computer-implemented method of  claim 9 , wherein the mean microvessel density threshold value is 0.057. 
     
     
         11 . The computer-implemented method of  claim 1 , wherein the method further comprises:
 processing the one or more ultrasound images to determine a microvessel tortuosity of the left and/or right testes or the mean thereof;   comparing the determined microvessel tortuosity to a microvessel tortuosity threshold representing a healthy control; and   outputting a diagnosis of hypogonadism when the determined microvessel tortuosity is greater than the threshold.   
     
     
         12 . The computer-implemented method of  claim 11 , wherein the microvessel tortuosity threshold is 3.2 C/L. 
     
     
         13 . The computer-implemented method of  claim 12 , wherein the method further comprises:
 receiving a sequence of microbubble-contrast ultrasound images;   processing the sequence of microbubble-contrast images to determine a plurality of microbubble trajectories; and   calculating the tortuosity of the microbubble trajectories to determine the microvessel tortuosity.   
     
     
         14 . The computer-implemented method of  claim 1 , wherein the method further comprises:
 processing the one or more ultrasound images to determine a microvessel diameter in the left and/or right testes or the mean thereof;   comparing the determined microvessel diameter to a microvessel diameter threshold representing a healthy control; and   outputting a diagnosis of hypogonadism when the determined microvessel diameter is reduced compared to the threshold.   
     
     
         15 . The computer-implemented method of  claim 14 , wherein the method further comprises:
 processing the one or more ultrasound images to determine a microvessel diameter;   comparing the mean microvessel diameter to a mean microvessel diameter threshold, wherein the mean microvessel diameter is between 70 and 120 μm; and   outputting a diagnosis of hypogonadism when the determined mean microvessel diameter is below the mean microvessel diameter threshold.   
     
     
         16 . The computer-implemented method of  claim 1 , wherein the method further comprises:
 processing the one or more ultrasound images to generate a microvessel image; and   determining the one or more testicular parameters based on the microvessel image.   
     
     
         17 . The computer-implemented method of  claim 16 , wherein the method further comprises:
 receiving a sequence of ultrasound images collected using contrast-enhanced ultrasound (CEUS) and/or super-resolution ultrasound (SRUS) receiving a sequence of ultrasound images;   processing the sequence of ultrasound images to determine a microbubble signal;   generating the microvessel image using the determined microbubble signal; and   calculating the one or more testicular parameters using the microvessel images, wherein the one or more testicular parameters each comprise a measurement of a feature of a microvessel morphology.   
     
     
         18 . (canceled) 
     
     
         19 . A system comprising an ultrasound imaging device and a processor, wherein the processor is configured to:
 receive one or more ultrasound images collected by the ultrasound imaging device using contrast-enhanced ultrasound (CEUS) and/or super-resolution ultrasound (SRUS);   determine one or more testicular parameters from the one or more ultrasound images;   compare the one or more parameters to one or more threshold values of the one or more parameters;   determine a difference between the one or more parameters and the one or more threshold values; and   output an indication of testicular function based on the comparison of the one or more parameters with the one or more threshold values.   
     
     
         20 . (canceled) 
     
     
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         34 . A composition for use in treating infertility or sub-optimal fertility of a male subject, wherein the composition comprises an anabolic-androgenic steroid, human chorionic gonadotropin (hCG), clomiphene citrate, aromatase inhibitors, or androgen receptor modulators; and wherein the subject has been determined to have reduced density, elevated tortuosity and/or reduced diameter of microvessels within the testes compared to healthy control. 
     
     
         35 . (canceled) 
     
     
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         42 . The system of  claim 19 , wherein the ultrasound imaging device is configured to obtain contrast-enhanced ultrasound (CEUS) and/or super-resolution ultrasound (SRUS) at a frequency range of 5-18 MHz.